1. Field of the Invention
The present invention relates to a novel cycloalkane derivative, a pharmacologically acceptable salt, or a hydrate thereof, useful as a pharmaceutical, particularly, with an analgesic action. The present invention further relates to a method for treating and/or preventing pain by administering the novel cycloalkane derivative of the present invention. The present invention also relates to the compound, a pharmacologically acceptable salt, or a hydrate thereof, for treating and/or preventing the crisis of a sodium channel associated disease. In addition, the present invention relates to a method for treating and/or preventing a sodium channel associated disease by administering the novel cycloalkane derivative of the present invention.
2. Description of the Related Art
A variety of pains including acute pain such as inflammatory pain and nociceptive pain; intractable chronic pain such as neurogenic pain, myogenic pain and fibromyalgia; and phantom limb pain probably derived from a psychogenic factor are known as pathologic pains. Since pain greatly degrades the quality of life of a patient in many cases, social loss caused by pain is incalculable.
Currently, nonsteroidal analgesics, nonnarcotic analgesics, narcotic analgesics, antiepileptic drugs and antidepressants are used as therapeutic agents for pain. Although a method for treating most cases of inflammatory pain and nociceptive pain has been established, there are very limited effective therapeutic agents for chronic pains such as neurogenic pain for which a nonsteroidal antiinflammatory drug is ineffective and which is resistant to narcotic analgesics.
Pregabalin and the like are currently used as therapeutic agents for neurogenic pain, but it is reported that pregabalin shows an effective therapeutic ratio based on self-evaluation of patients of painful diabetic neuropathy of approximately 50% (Non Patent Literature 1), and hence, it cannot be said that patient satisfaction with treatment is always attained.
Voltage-gated sodium channels (Nays) are ion channels each including an α subunit having four domains and auxiliary β subunits, at least nine subtypes thereof have been reported so far, and these subtypes respectively have different expression distributions and physiological actions so as to regulate biological functions.
The sodium channels are an essence of neural activity, and drugs such as a local anesthetic of lidocaine, an antiarrhythmic of mexiletine and an antiepileptic of carbamazepine are known as inhibitors of the sodium channels. Such drugs have, however, low selectivity for the Nav subtypes. Since sodium channels of different subtypes are expressed in muscles, cardiac muscle cells and the central nervous system as shown in Table 1, there arises a problem of an adverse drug action caused when such a drug is systemically administered.
TABLE 1SubtypeMain expression siteNav1.1Central nervous systemNav1.2Central nervous systemNav1.3Central nervous systemNav1.4Skeletal muscleNav1.5Cardiac muscle cellsNav1.6Sensory/motor nervous systemNav1.7Sensory nervous systemNav1.8Sensory nervous systemNav1.9Sensory nervous system
On the other hand, it is known that Nav 1.7 defect causes pain insensitivity in a human (Non Patent Literature 2), and since similar tendency is observed in KO mice (Non Patent Literature 3), it is regarded that a Nav 1.7 selective inhibitor is a promising target of therapeutic agents for various pains.
Patent Literature 1 relates to a Nav 1.7 modulator and specifically describes, for example, a compound represented by formula (A) below (in Example 811). The feature of the compound described in this patent literature is that two aromatic rings are connected through an oxygen atom, and further, N-substituted sulfonamide is connected to one of the aromatic rings (phenyl group). The compound of the present invention differs therefrom in that cycloalkane is connected to an aromatic ring through an oxygen atom. Patent Literature 1 neither describes nor suggests the structure of the compound of the present invention.

Specifically, the compound disclosed in Patent Literature 1 is described in the claim as falling within a structure represented by formula (B) below. The moiety B in this structure is defined as “phenyl or Het2, wherein Het2 is defined as a 5- or 6-membered aromatic heterocyclic group containing (a) one to four nitrogen atoms, (b) one oxygen atom or one sulfur atom, or (c) one oxygen atom or one sulfur atom and one or two nitrogen atoms”. Thus, the moiety B is an aromatic substituent. The patent literature neither discloses that this moiety is a saturated substituent nor discloses that cycloalkane is formed.

Patent Literature 2 relates to an N-type calcium channel inhibitor and specifically describes, for example, a compound represented by formula (C) below (in Example 5(11)). The compound described in this patent literature has a structure in which an aromatic ring and a saturated heterocyclic ring are connected through a polymethylene(oxy) chain. An N-substituted sulfonamide is bonded to aromatic ring (phenyl group), and two substituents are further introduced in the nitrogen atom of this sulfonamide. Specifically, the feature of this compound is that the nitrogen atom of the sulfonamide is di-substituted. The compound of the present invention differs therefrom in that: a saturated ring is not a heterocyclic ring; cycloalkane and an aromatic ring are connected through an oxygen atom and not through a polymethylene chain; and a sulfonamide moiety is mono-substituted at its nitrogen atom. Patent Literature 2 neither describes nor suggests the compound of the present invention at all.

Neither does the compound of the present invention fall within a structure represented by formula (D) below described in claims of the Patent Literature 2, nor the structure of the compound of the present invention is suggested from the description related to this structure.
